Racemic-diketone compounds

ABSTRACT

This invention is directed to racemic-diketone compounds of the formula:   WHEREIN R1 and R2 are lower alkyl, araklyl and taken together form a lower alkylene radical and R3 and R4 are lower alkyl, aralkyl, and taken together form a lower alkylene radical; useful in a stereoselective synthesis of the food additive mesonordigydroguaiaretic acid from a protected ortho dihydroxy benzene.

United States Patent [191 Perry 1 Oct. 22,1974

[ RACEMlC-DIKETONE COMPOUNDS [75] inventor: Clark William Perry, SaddleRiver,

[73] Assignee: Hoffman-La Roche lnc., Nutley,

[22] Filed: Jan. 17, 1973 [21] App]. No.: 324,253

Related US. Application Data [62] Division of Ser. No 782,414, Dec. 9,1968. Pat. No.

UNITED STATES PATENTS 10/1973 Perry 260/3478 PQEIPQW e fo mul PrimaryExaminer-Daniel D. Horwitz Attorney, Agent, or Firm-Samuel L. Welt; JonS. Saxe; William H. Epstein [57] ABSTRACT This invention is directed toracemic-diketone comwherein R, and R are lower alkyll, araklyl and takentogether'form a lower alkylene radical and R and R are lower alkyl,aralkyl, and taken together form a lower alkylene radical; useful in astereoselective synthesis of the food additive meso-nordigydroguaiareticacid from a protected ortho dihydroxy benzene.

3 Claims, N0 Drawings 1 RACEMIC-DIKETONE COMPOUNDS cRoss REFERENCE TORELATED I APPLICATIONS This application is a division of the copendingapplication Ser. No. 782,414, filed Dec. 9, I968, entitledSTEREOSELECTIVE TOTAL SYNTHESIS OF MESO-NORDIHYDROGUAIARETIC .ACID", nowUS. Pat. No. 3,769,350.

BACKGROUND OF THE INVENTION In the past, meso-nordihydroguaiaretic acid[meso- 4,4'(2,3-dimethyltetramethylene)-dipyrocatechol] has found onlylimited use as a food additive and antioxidantdue to the expenseof itsproduction. This is true 15 since meso-nordihydroguaiarectic acid whichhas the formula:

has been difficult to synthesize commercially. The only acceptablecommercial method for its production has been by extraction fromLarreadivaricata, the creosote bush, which is found in the southwest UnitedStates. This procedure has proven extremely disadvantageously due to thefact that nordihydroguaiaretic acid occurs only in small quantities inthis plant. Therefore,

a great quantity of plant material must be utilized in order to isolatea small quantity of natural nordihydroguaiaretic acid. Additionally, theprocess whereby nordihydroguaiaretic acid .is isolated from Lq'rreadivaricata has proven extremely cumbersome and uneconomical. Up untilthe present time, there has been no successful commercial process fordirectly chemically synthesizing nordihydroguaiaretic acid withoutisolating it from its natural source.

SUMMARY OF THE INVENTION I This invention is directed tostereoselectively synthesizing meso-nordihydroguaiaretic acid from acompound of the formula: i

10. wherein R, and R are lower alkyl, aralkyl, and taken together form alower alkylener'adical.

By means of this process, nordihydroguaiaretic acid can be produced fromthe compound of Formula II above economically and in high yields.

DETAILED DESCRIPTION OF THE INVENTION As used throughout thisapplication, the term, lower a alkyl," comprehends both straight andbranched chain hydrocarbon groups containing from one to six carbon termlower alkylene includes both straight and branched chain alkyleneradicals containing from two to six carbon atoms such as methylene,ethylene, propylene, butylene, isobutylene, etc. Theterm lower alkanoylincludes alkanoyl groups containing from one 1 to six carbon atoms suchas acetyl, propioriyl, formyl,

1 and butyryl. The term aralkyl includes aralkyl groups 5 containingfrom seven to I4 carbon atoms such as phenyl lower alkyl, i.e., benzyl,phenylethyl, etc. The term halogen includes all four halogens, i'.e.,iodine, bromine, chlorine and fluorine.

In the structural formulae given throughout the application, thesubstituents which are attached to the molecule above the plane of themolecule are designated by 1 atoms such as methyl, ethyl, propyl,isopropyl, etc. The

Qand the substituents which are attached to the molecule beloyt theplaneof the molecule are desigiated by lriaEcordance with thisinvention, a compound of the Formula I above is prepared from a compoundof the 0 Formula [1 above by means of the following reaction wherein Rand R are as above, and R and R are sei lected from the group.consisting of lower al kyl, aralkyl,

and taken together form a lower alkylene radical.

The reaction of step (a) wherein the compound of the Formula II above isconverted to the compound of the Formula III above has been previouslycarried out by reacting the compound of Formula I above with propionylchloride via a Friedel-Crafts reaction. By utilizing this process thecompound of Formula III above is 1 produced in yields of at most 65percent.

In accordance with this invention, it has been found that the compoundofFormula II can be reacted with propionyl chloride or. propionicanhydride and converted to the compound of Formula III in yields as highas 95 percent. This process is first carried out by reacting thepropionic anhydride or propionyl chloride with a Friedel-Crafts catalystin the presence of a halogenated hydrocarbon solvent to form a complex.In accordance withthe process of this invention, the compound of FormulaII is added to the complex. Upon the addition of the compound of FormulaII to the complex, these materials react to form the compound of FormulaIII above. i i

The complex is simply formed by adding propionyl chloride or propionicanhydride 'to a Friedel-Crafts catalyst. In carrying out this reaction,any conventional inert halogenated hydrocarbon solvent such aschloroform, methylene chloride, carbon tetrachloride, etc., can beutilized. Any conventional Friedel-Crafts catalyst can be utilized.Among the conventional Friedel- ZCrafts catalysts which can be utilizedin accordance 'with this invention are aluminumchloride, aluminumbromide, stannic chloride, stannous chloride, zinc chloride, antimonytrichloride, etc. In carrying out this re action, temperatures of from 15C. to 35C. should be utilized. Generally, it is preferred to carry outthis reaction at C. to C.

The compound of Formula III above is prepared from the complex by simplyadding the compound of Formula -II above to this complex. This reactionis carried out in the same inert halogenated hydrocarbon solventutilized to form the complex. In carrying out this reaction,temperatures of from-about l5C. to 35C. can be utilized, with 0C.] to5C. being preferred. In obtaining the compound of Formula III in highyields and high purity from the compound of Formula II above, it isnecessary to prepare the complex first before the addition ofthe'compound of Formula II above. It is by first preparing this complexand then reacting this complex with the compound of Formula II aboveinthe presence of the halogenated hydrocarbon solvent that the compound ofFormula III above can be prepared in yields as high as percent.

In carrying out the reaction of step (b) wherein a compound of theFormula Ill above is converted to a compound of the Formula IV, the samesolvents that were utilized in step (a) can be utilized in thisreaction.

The reaction of step b) is carried out by treating the compound of theFormula III above with bromine in I the presence of a halogenatedhydrocarbon solvent such as chloroform, carbon tetrachloride, etc. Anyconventional halogenated hydrocarbon solvent can be utilized in carryingout this reaction. This reaction is carried out atthe reflux temperatureof the reaction medium. In carrying out this reaction from about 1.0 toabout 1.05 moles of bromine, preferably 1.02 moles of bromine areutilized per mole of the compound of Formula III above. In accordancewith this invention, it has been found that by utilizing refluxtemperatures, a mole ratio of from 1.00 to 1.05 moles of bromine permole of the compound of Formula III above, and halogenated hydrocarbonsolvents yields as high as 96 percent of the compound of Formula IVabove can be obtained.

The compound of Formula IV above is converted to the compound of FormulaV above by reacting the compound of the Formula IV above with a compoundof the formula:

I M-l- Rio v IV-A be utilized in carrying out this reaction. Generally,it is.

preferred to utilize bases such as alkali metal hydrides nd and? has? ofdeferrals;

wherein M is as above and R is hydrogen or lower allcyl.

Among the preferred alkalimetal hydrides are included sodium hydride,potassium hydride, etc. Among the preferred amide bases of Formula Xabove which can be utilized in this invention are included potassiumamide, sodamide, sodium methylamide. Generally, it is preferred to carryout the reaction in aninert low boiling solvent such as a' liquidammonia. However, any conventional inert solvent can be utilized. Incarrying out this reaction, temperature and pressure are not critical.Temperatures of from'about 0C. to 100C. can be utilized in carrying outthis reaction, depending t upon the reflux temperature of the solvent.

The reaction of compounds of the Formula lV-A with compounds of theFormula IV to produce a compound of the Formula V is carried out in thepresence of a solvent. Any conventional inert solvent can be utilized inthis reaction. Among the conventional inert organic solvents which canbe utilized in this reaction are hydrocarbons such as benzene, toluene,xylene, and the like; chlorinated hydrocarbons such as chlorobenzene andthe like; ethers such as tetrahydrofuran, diethyl ether, dioxane and thelike. inorganic solvents such as liquid ammonia, which ispreferred,.canalso be utilized. ln carrying out this reaction, temperature andpressure are not critical and this reaction can be carried out at roomtemperature and atmospheric pressure. If desired, elevated temperaturesof reduced temperatures can also be utilized. Generally, it is preferredto utilize atemperature of from about -50C. to about 100C. dependingupon the reflux temperature of the solvent.

In accordance with this invention, it has been found that the reactionof step c) produces the compound of the Formula V above in yields ashigh as 90 percent.

The conversion of the'compounds of Formula V to compounds of the FormulaVl, via reaction step d'), is

carried out bytreating.the compound of the Formula V with a strongacidic agent. Any conventional strong acidic agent can be utilized ineffecting the conversion of compounds of the Formula V to compounds ofFormula VI. Among the conventional acidic agents which can be utilizedin accordance with this invention are included hydrochloric acid,hydrobromic acid, sulfuric acid, acetic acid, p-toluene sulfonic acid,etc. in carrying out this reaction, it is preferred to utilize an inertorganic solvent. Any conventional inert organic solvent can be utilized.Among the conventional inert organic solvents which can be utilized inaccordance with this invention are included methanol, ethanol, as wellas the organic solvents hereinbefore mentioned. ln carrying out thisreaction, temperature and pressure are not critical, and this reactioncan be carried out at room tem perature or elevated or reducedtemperatures. Generally, it is preferred to carry out this reaction at atemperature of from 0C. to 100C.

In accordance with a preferred embodiment of this invention, thecompound of Formula V above can be converted into the compound ofFormula Vl above, via reaction step (d), so as to produce a compound ofFormula Vl above in yields as high as 96 percent. It has been found thatwhen the compound of Formula V above is treated with an alcoholicsolution containing This improved embodiment of the reaction of step(d)' is carried out at the reflux temperature of the reaction medium. ia r In the past, the compound of the Formula Vl has been convertedto.compounds of the Formula Vlll by hydrogenation in the presence of apalladium catalyst, preferably palladium oxidein an alcoholic or organicacid solvent such as acetic acid, methanol, etc. However, by thisprocess, the compound of the Formula Vlll above has only been obtainedin yields of at most 30 percent. Furthermore, in this reaction manybyproducts are formed which contaminate the final product and aredifficult to separate therefrom. In accordance with this invention, ithas been found that when the compound of the Formula Vi above ishydrogenated in the presence of a catalyst selected from the groupconsisting of palladium oxide, palladium chloride, hydrogenatedpalladium chloride or hydrogenated palladium oxide in an organic etheror estersolvent, compounds of the Formula Vlll above are obtained inyields. as high as 80 percent. The hydrogenated palladium chloride andpalladium oxide catalysts are formed by well-known techniques of mixingpalladium oxideor palladium chloride with hydrogen gas in the presenceof aconventional inert organic solvent such as mentioned hereinbefore.The useof etheror ester solvents in the reaction of step (e)substantially eliminates the formation of undesired non-separableby-produ'cts. The preferred solvent for use in this invention istetrahydrofuran or ethyl acetate. However, any of the otherconventionalorganic ether or ester solvents can be utilized in accordance with thisinvention. Among the other conventional organic ether or estersolventswhich can Ebe utilized in accordance with this invention areincluded dioxane, diethylether, etc. Generally, this reaction is carriedout at a temperature of from about 0C. to C, depending upon the refluxtemperature of the solvent.

lnutilizing palladium chloride in step (c), it is desirable toincorporate an inorganic buffering agent in the catalyst system. Anyconventional inorganic buffering agent can be utilized in the catalystsystem of step (e). Among the inorganic buffering agents which can beutilized in step (e) are included sodium acetate, potassium acetate,sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassiumcarbonate, etc. These inorganic buffering agents generally contain analkali metal. The buffering agent is present in thecatalyst system in anamount of 0.9 to 2 equivalents per equivalent of chloride ion containedwithin the palladium chloride catalyst.

ln converting the compound of the Formula Vl above to the compound ofthe Formula Vl-l above via reaction step (f), the compound of theFormula Vl above is bydrogenated in the presence of palladium as acatalyst. The palladium catalyst can be utilized alone or in combinationwith any of the conventional catalyst supports such as carbon black,calcium carbonate, or barium carbonate. in carrying out this reaction,it is generally preferred to utilize alcoholic solvents such asmethanol,

ethanol, etc. In carrying out the reaction of step (I),

temperatures of from 50C. to 125C. and pressures of above to compoundsof the Formula VIII above, via reaction step (g) is carried out byhydrogenating the compound of the Formula Vll above in the presence of apalladium chloride or palladium oxide catalyst utilizing an organicether or ester inert solvent. The same conditions and catalysts thatwere utilized in carrying out reaction step (e) are utilized in carryingout the reaction of step (g).

When any one of R R R and R in the compound of the Formula VIII aboveare lower alkyl or aralkyl, the compound of the Formula VIII above canbe converted to the compound of the Formula I above via reaction step(b) by means of treating thecompound of the Formula VIII above with ahydrolyzing agent. Any conventional means of ether hydrolysis can be'utilized to convert the compounds of Formula VIII above to the compoundof the Formula I above. Generally, it is preferred to utilize ahydrolyzing agent such as hydroiodic acid, hydrobromic acid, pyridinehydrochloride or boron tribromide in the presence or absence of an inertorganic solvent. Any conventional inert organic solvent can be utilizedin carrying out this reaction. In carrying out this reaction,temperature and pressure are not critical and the hydrolysis reactionmay be carried out at room temperature and atmospheric pressure or atelevated and reduced temperatures or pressures.

When either R and R or R and R form lower alkylene moieties in thecompound of the Formula VIII above, the compound of the Formula VIIIabove is converted to the compound of the Formula I above, via reactionstep (h), by treating the compound of the Formula VIII above with anether hydrolyzing agent in the same manner mentioned above in connectionwith R,,

R R and R being lower alkyl.

In accordance with another embodiment of this invention, the compound ofFormula VII above can be converted into the compound of Formula VIIIabove by the following reaction scheme:

CH3 CH3 V V R10 b 4 -OR;

R30 -OR4 VII l RiO ' I A E OR:

OH CH:

XI l (I) 5 CH3 Rio I A E ORa 0R5 CH:

XII il wherein R,, R R and R are as above, and R is a lower alkanoyl.

The compound of Formula VII is converted to the compound of Formula XIvia reaction step (i), by treating the compound of the Formula VII withan alkali metal in liquid ammonia. In carrying out this reaction, sodiumand potassium are the preferred alkali metals. Generally, it ispreferred to have an inert organic solvent present in the reactionmedium. Among the conventional inert organic solvents which may bepresent in the reaction medium, tetrahydrofuran is preferred.

Generally, this reaction'is carriedout at a temperature of from about50C. to 30C.

The compound of Formula XI above is converted to the compound of FormulaXII above via reaction step (j) by treating the compound of Formula XIabove with an esterifying agent. Among the esterifying agents which canbe utilized are included organic acid anhydrides or organic acidhalides. Generally, this esterification reaction is carried out in thepresence of an organic amine base. Among the conventional organic aminebases which can be utilized in accordance with this invention areincluded trimethylamine, pyridine, triethylamine. In carrying out thisreaction, temperature and pressure are not critical and this reactioncan be carried out at room temperature or at elevated or reducedtemperatures. Generally, it is preferred to utilize the temperature offrom 0C. to 100C.

The compound of Formula XII can be converted to the compound of FormulaVIII above by hydrogenation, as in step (k), by utilizing the sameconditions set forth with respect to step (e). This hydrogenation iscarried out in the presence of a catalyst utilizing an inert ether orester solvent as in step (e).

In accordance with another embodiment of this invention, the compound ofFormula XI above can be directly converted into the compound of FormulaVIII above by hydrogenation. This hydrogenation step is carried oututilizing the same conditions as in reaction step (k).

It is to be understood-that while the-structural formulae of compoundsof the Formulae V, VII, VIII, XI and XII are shown to represent aspecific enantiomer, these formulae can also represent the antipode orracemic mixture thereof. It is apparent that the compound of Formula Iabove can be prepared from any of the optically active isomers of thecompounds of Formulae V, VII, VIII, XI and XII as well as racemicmixtures thereof. This is true since all of the compounds of Formulae V,VII, VIII, XI and XII are converted to the symmetrical end product ofFormula I above. The desired optically active antipodes of the compoundsof Formulae V, VII, VIII, XI and XII above can be obtained from theirracemic mixtures by standard resolution techniques.

The invention is further illustrated by the following examples. Alltemperatures are in degrees centigrade. Percent is given in percent byweight.

EXAMPLE 1 3,4-Dimethoxy-propiophenone To a cooled, well-stirred slurryof anhydrous aluminum chloride (22.0 g., 0.166 mole) in chloroform ml.)at 05C. under an atmosphere of dry nitrogen, was added a solution offreshly distilled propionyl chloride 12.0 g., 0.13 mole) in chloroform10 ml.) at such a rate as to maintain a temperature of 0-5C. When theaddition was complete (about 15 min.), a solution of 1,2-dimethoxybenzene (13.8 g., 0.1 mole) in chlo- (90.3 percent yield). 7

1 i roform (10 ml.) wasa dded iri tlie same manner over a 30 minuteperiod, during which time hydrogen chloride was slowly evolved. Thereaction mixture became a nearly clear yellow-green solution, which wasstirred at 05C. for 1 hour after completion of the addition. Withcontinued stirring and cooling, 3N hydrochloric acid (100 ml.) was thenadded very cautiously dropwise, keeping the temperature below 30C. Whenall the solids were dissolved, the phases were separated, the lowerorganic phase was washed with 3N sodium hydroxide solution (50 ml.)once, and the two aqueous solutions were back-extracted in successionwith chloroform (50 ml.). The combined chloroform solution.

was dried over anhydrous magnesium sulfate, filtered, evaporated todryness in vacuo, and the residue was crystallized from methanol (25ml.) by chilling overnight in a freezer to yield 18.15 grams of3,4dimethoxy-propiophenone (93.8 percent yield).

EXAMPLE2 a-Bromo-3,4-dimethoxy propiophenone A solution of bromine (65.4g., 0.408 mole, 2 percent excess) in chloroform 100 ml.) was added asrapididly as possible through an addition funnel to a refluxing solutionof 3,4-dimethoxy propiophenone (77.6 g., 0.40

mole) in chloroform (300 ml.) with good agitation. The

hydrogen bromide which was rapidly evolved was con-.

EXAMPLE 3 Racemic-2,3-dimethyl-1 ,4-bis-( 3 ,4-dimethoxyphenyl 1,4-butanedione To liquid ammonia (approximately 50 ml.) was addedpowdered ferric chloride (50 mg), then small pieces of sodium (0.51 g.,0.022 g-atom, 10 percent excess) were added and the blue color allowedto dissipate over about a 20 minute period. To the resulting graysuspension of sodamide was added solid 3,4- dimethoxy propiophenone(3.88 g., 0.02 mole) in small portions and the mixture was stirred about5 minutes. Solid a -bromo-3,4-dimethoxy propiophenone (5.46 g., 0.02mole) was then added in small portions to the gray-green mixture, andthe reaction mixture turned deeper green, then reddish, and finally tancolored. After the mixture was stirred 1 hour, solid ammonium chloride(2.68 g.) was added, followed by dichloromethane (50 ml.) and the graymixture was then warmed cautiously to room temperature to evaporate mostof the ammonia. The mixture was filtered with suction, the residualsolids were extracted twice with dichloromethane, and the combinedfiltered solutionswere concentrated to about 50 ml. in volume, dilutedwith methanol (75 ml.), and further concentrated to about 50 ml. involume by boiling. 6.96 Grams ofracemic-2,3-dimethyl-1,4-bis(3,4-dimethoxyphenyl)- 1,4-butanedionecrystallized on stirring and cooling EXAMPLE 43,4-Dimethyl-2,5.-bis(3,4-dimethoxyphenyl)-furan To a boiling solutionof racemic-2,3-dimethyl-l,4-

10 bis(3,4-dimethoxyphenyl)-1,4-butanedi0ne (38.6 g., 0.10 mole) indichloromethane ml.) was added a 1 percent solution of hydrogen chloridein methanol (250 ml.) slowly with continued boiling. After about 5minutes boiling, crystals separated and after chilling the slurry, 30.20grams of 3,4-dimethyl-2,5-bis(3,4- dimethoxyphenyl)-furan was obtained(82 percent yield). Concentration of the mother liquors afforded 4.56grams of 3,4-dimethyl 2,5-bis(3,4-dimethoxyphenyl)-furan (12.4 percentyield). Further concentration afforded 0.5 grams of 3,4-dimethyl-2,5bis-(3,4-dimethoxyphenyl)-furan 1.5 percent yield);

EXAMPLE 5 All cis-3 ,4-dimethyl-2,5-bis( 3 ,4-dimethoxyphenyltetrahydrofuran Hydrogenation of the3,4-dimethyl-2,5-bis(3,4-dimethoxyphenyl)-furan (36.8 g., 0.1 mole) over10 percent palladium on calcium carbonate catalyst (5.0 g.) inethanol(1,000 ml.) at C. under 1,500 p.s.i.g. hydrogen for 3 hours, followed byfiltration and removal of solvents gave a white solid (35 g.) which onrecrystallization from methylene chloride-methanol gave 29.8 g. of allcis-3,4-dimethyl-2,5-bis(3,4dimethoxyphenyl)- tetrahydrofuran (80.4percentyield). Concentration of the mother liquors gave a second crop(2.54 g., 6.8 percentyield) and a third crop (0.47 g., 1.3 percentyield).

EXAMPLE 6 r The procedure wherein all cis-3,4-dimethyl-2,5bis(3,4-dimethoxyphenyl)-tetrahydrofuran and 3,4-dimethyl-2,5-bis(3,4dimethoxyphenyl)-furan is hydrogenated is asfollows: i

A mixture of the compound to be reduced (2.0-4.0 g.), catalyst (usually0.2 g.) and solvent (50 ml.) was agitated magnetically under anatmosphere of hydrogen at the desired temperature. After filtration ofthe spent catalyst, the filtrate was examined by gas chromatographicanalysis (4 feet X 54 inch O.D. copper column packed with 1.1 percentSE-30 +0.2 percent Versamid 900 on AW/DMCS chromosorb G, 60-80 mesh;l'le carrier gas; 220-250C.). For isolation of meso- 2,3-dimethyl-1,4-bis( 3,4-dimethoxypheny1)-butane, the solvents were removed and theresidue was crystallized from 10-20 times its weight of hexane.

a. Preparation of meso-2,3-dimethyl-l,4-bis(3,4-dimethoxyphenyl)-butanefrom 3,4dimethyl-2,5-bis(3,4- dimethoxyphenyl )-furan 33.3 g. (90.5mmoles) of 3,4-dimethyl-2,5-bis(3,4- dimethoxyphenyl)-furan intetrahydrofuran (500 ml.) was hydrogenated over powdered palladium oxide(2.0 g.) at 50C./1,500 p.s.i.g. for about 10 hours. Gas chromatographicanalysis indicated 77.8 percent of the product in the crude filtrate.Removal of solvent and crystallization of the residue (33.7 g.) fromhexane (550 ml.) gave meso-2,3-dimethyl l,4-bis(3,4-dimethoxy-phenyl)-butane (25.4 g., 78 percent yield). b. Preparation ofmeso-2,3-dime thyll ,4-bis(3,4-dimethoxyphenyl)-butane from allcis-3,4-dimethyl-2,5- bis( 3 ,4-dimethoxyphenyl )-tetrahydrofuran 745mg. of all cis-3,4-dimethyl-2,5bis(3,4-dimethoxyphenyl)-tetrahydrofuran(2 mmoles) in tetrahydrofuran (50 ml.) was hydrogenated over powderedpalladium oxide (200 mg.) at 25/l atm. for 46 hours. Gas chromatographicanalysis indicated. 78.5 percent product in the crude filtrate. Removalof solvent and crystallization of the residue (848 mg.) from hexane gave11 1 crystalline meso-2,3-dimethyl-1,4-bis(3,4-dimethoxyphenyl)-butane(543 mg, 76 percent yield).

EXAMPLE 7 O.D. copper column packed with 1.1 percent SE-30 silicone gumand 0.2 percent Versamid 900 on 60-80 mesh chromosorb G/AW-DMC S,programmed from 225C. to 275C. at 2/minute helium carrier gas at 60ml./min.) of the filtered reaction mixture was used to determinerelative yields. For isolation of meso-2,3- dimethyl-l ,4-bis(3,4-dimethoxyphenyl )-butane, the solvent was removed under reducedpressure, the residue was taken up in about 5 ml. warm dichloromethane,50 ml. hexane was added, and the solution was boiled down to a totalvolume of about 40 ml.

The following table lists the buffering agents utilized, if any,temperatures utilized, pressures utilized, and yields ofmeso-2,3-dimethyl-l,4-bis(3,4-dimethoxyphenyl)-butane obtained in theabove reaction:

Table Buffer Temp.C. H -Prcss., Relative Yield p.s.i.g. (%)hz.l/32(None) 75 1500 78 0.400 g. NaOAc 75 1500 82 0.420 g. NaOAc 75 1500 820.440 g. NuOAc 75 1500 85 0.460 g. NaOAC 75 1500 74 0.500 g. NaOAc 751500 81 0.600 g. NaOAc 75 I500 80 0.800 g. NaOAc 75 1500 79 0.440 g.NaOAc 75 300 80 0.440 g. NuOAc 75 150 79 0.460 g. NaOAc 75 50 79 0.440g. NuHCO 75 1500 80 EXAMPLE 8 Meso 4,4-(2,3-dimethyltetramethylene)-dipyrocatechol Concentrated hydrobromic acid (860 g.) was addedunder'nitrogen to meso 2,3-dimethyl-l,4-bis(3,4-dimethoxyphenyl)-butane(71.56 g., 0.201 mole) and the mixture was stirred and refluxed for 9hours and allowed to cool to room temperature overnight with continuedstirring. The dark colored solid product, collected by filtration,washed with water and dried afforded the crude product, meso4,4'-(2,3-dimethyltetramethylene)-dipyrocatechol (59.27 g., 97.5 percentyield). Recrystallization from about 1,600 ml. of 20 percent aqueousacetic acid with charcoal treatment gave a much lighter colored, butstill gray-brown, crystalline product, (45.74 g., 77 percent recovery,75 percent yield). A second recrystallization with charcoal gave lighttan crystals, (91 percent recovery). After a third recrystallization thecream-colored crystals (95 percent recovery) had m.p. 184.5 to 186,identical in all respects with purified naturalmeso-nordihydroguaiaretic acid, mixed m.p. 184186.

EXAMPLE 9 Sodium (4.37 g., 0.19 mole) was added to anhydrous1(R),2(S),3(S)-and liquid ammonia 1.1 1.) and stirred under reflux undera nitrogen atmosphere. After one hour, a solution of allcis-3,4-dimethyl- 2,5-bis( 3,4-dimethoxyphenyl )-tetrahydrofuran 18.6g., 50 mmoles) in tetrahydrofuran (500 ml.) was added. After 2.5 hoursof stirring under reflux, the ammonia was removed by warming thereaction mixture to room temperature. Addition of methanol (10 ml.) andthen water (400 ml.), followed by extraction with chloroform, washingwith water, drying over sodium sulfate, and removal of solvents gave thecrude product (22.0 g.) which was crystallized from methanol to affordwhite crystals of the racemic mixture of 1(R),2(S),3(S)- and1(S),2(R),3(R)-1,4-bis- (3,4-dimethoxyphenyl)-2,3-dimethyl-l-butanol17.96 g., 48.0 mmoles, 96.0 percentyield).

EXAMPLE 10 Racemic mixture of 1(R),2(S),3(S)- and1(S),2(R),3(R)-1,4-bis- (3,4-dimethoxyphenyl )-2,3-dimethyl- 1 -acetoxybutane EXAMPLE 1 l Hydrogenolysis of the racemic mixture of1(R),2(S),3(S)- and l(S),2(R),3(R)-1,4-bis(3,4-dimethoxyphenyl)-2,3-dimethy1-1 -acetoxy butane A mixture of the racemicmixture of 1(R),2(S),3(S)- and1(S),2(R),3(R)-1,4-bis(3,4-dimethoxyphenyl)- 2,3-dimethyl-l-acetoxybutane (1.045 g., 2.5 moles), ethyl acetate (50 m1.), and powderedpalladium oxide mg.) was hydrogenated at room temperature and 1 atm. for22 hours. Filtration and removal of solvent gave 1.015 g. of oil whichwas crystallized from hexane to give 0.703 g. of meso2,3-dimethyl-1,4-bis(3,4-dimethoxyphenyl)-butane (1.96 mmoles, 79percent) as a white solid.

butane,

I claim: 1. A compound of the formula:

ll V R10 CCHCHC -ORa A ll CH3 0 R20 0R4 wherein R and R are lower alkyl,and aralkyl, and R and R are lower alkyl, aralkyl, its antipode andracemic mixtures thereof.

2. The compound in accordance with claim 1 wherein R R R and R aremethyl.

3. The compound in accordance with claim 1 wherein said compound isracemic 2,3-dimethyl-l,4- bis( 3,4-dimethoxyphenyl) 1,4-butanedione.

1. A COMPOUND OF THE FORMULA:
 2. The compound in accordance with claim 1wherein R1, R2, R3 and R4 are methyl.
 3. The compound in accordance withclaim 1 wherein said compound is racemic2,3-dimethyl-1,4-bis(3,4-dimethoxyphenyl)1,4-butanedione.